The purpose of this Neuropathology Core (NPC) is to support and promote the proposed projects with histopathology, quantitative stereology, immunohistochemistry and electron microscopy of the various transgenic mouse models of sporadic and familial Alzheimer's disease (AD) under study. In addition, the core will provide sporadic AD, FAD and control human postmortem brains to evaluate for the presence of endosomal/lysosomal abnormalities, which is central to some of these projects. The mouse brains will be subjected to a battery of staining procedures and morphological analysis. Amyloid plaques, preamyloid lesions, vascular amyloid and neuronal pathology will initially be visualized by Bielschowsky silver and Thioflavin S stainin. Application of the optical dissector technique will provide quantitation of parenchymal and vascular Abeta deposition, as well as neuronal pathology. Regional cell loss will also be quantitated, with the data being applied in these projects. In addition, the NPC will provide electron microscopic (EM) expertise. EM morphological and immunocytochemical analyses on transgenic mouse brains and transfected cell models of AD will be correlated with the light microscopic immunocytochemical studies of antigens involved in endosomal/lysosomal up-regulation and protein and membrane trafficking, performed within the context of some projects. EM will also assess if Abet deposits are fibrillar or amorphous. Furthermore, in mice subject to ischemia, the area of infarction will be quantitated as part of the NPC. To correlate with the morphometric studies, the NPC will also coordinate all Abeta40 and Abeta42 ELISA measurements, in some projects. Since the ELISA only gives quantitative data regarding the carboxyl terminus of the peptide, immunoprecipitation mass spectroscopy will also be used to identify the Abeta peptide species present in the transgenic mice biological fluids. The latter will provide valuable information regarding the Abeta peptides involved in the progression of Abeta deposits from preamyloid to amyloid and identify Abeta species in endosomes. The above studies, quantitating the degree of AD-related pathology histologically, by EM and biochemically will be essential for each of these projects in this program.